NK Cell Induced T Cell Anergy Depends on GRAIL Expression.

Grazyna Galazka,Anna Jurewicz,Alicja Ewiak-Paszynska,Malgorzata Domowicz

doi:10.3390/cells8080790

Grazyna Galazka, Anna Jurewicz + Show 2 more

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https://doi.org/10.3390/cells8080790

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Journal: Cells	Publication Date: Jul 29, 2019
Citations: 4	License type: CC BY 4.0

Affiliation: Medical University of Lodz

Abstract

NK cells (natural killer cells) being a part of the innate immune system have been shown to be involved in immunoregulation of autoimmune diseases. Previously we have shown that HINT1/Hsp70 treatment induced regulatory NK cells ameliorating experimental autoimmune encephalomyelitis (EAE) course and CD4+ T cells proliferation. NK cells were isolated from mice treated with HINT1/Hsp70 and co-cultured with proteolipid protein (PLP)-stimulated CD4+ T cells isolated from EAE mice. Cell proliferation was assessed by thymidine uptake, cytotoxicity by lactate dehydrogenase (LDH) release assay and fluorescence activated cell sorting (FACS) analysis, protein expression by Western blot, mRNA by quantitative RT-PCR. Gene related to anergy in lymphocytes (GRAIL) expression was downregulated by specific siRNA and GRAIL overexpression was induced by pcDNA-GRAIL transfection. HINT1/Hsp70 pretreatment of EAE SJL/J mice ameliorated EAE course, suppressed PLP-induced T cell proliferation by enhancing T cell expression of GRAIL as GRAIL downregulation restored T cell proliferation. HINT1/Hsp70 treatment induced immunoregulatory NK cells which inhibited PLP-stimulated T cell proliferation not depending on T cell necrosis and apoptosis. This immunoregulatory NK cell function depended on NK cell expression of GRAIL as GRAIL downregulation diminished inhibition of NK cell suppression of T cell proliferation. Similarly GRAIL overexpression in NK cells induced their regulatory function. HINT1/Hsp70 treatment generated regulatory NK cells characterized by expression of GRAIL.

Highlights

The cells of an adaptive immune system, in contrary to cells of an innate immune system, have been regarded as cells creating immunological memory after an initial response to a specific pathogen leading to an enhanced response to subsequent encounters with that pathogen
The proliferation of CD4+ T cells isolated from EAE mice stimulated with PLP139–151 was inhibited by coculture with NK cells isolated from mice injected with HINT1/Hsp70 but not by NK cells isolated from C3/Hsp70 injected mice (Figure 1b)
This inhibitory effect of NK cells isolated from mice treated with HINT1/Hsp70 on PLP139–151 -induced proliferation of CD4+ T cells did not depend on cytotoxicity of NK cells as we have not seen necrosis or apoptosis of CD4+ T cells induced in co-culture system (Figure 1c,d)

Summary

Introduction

The cells of an adaptive immune system, in contrary to cells of an innate immune system, have been regarded as cells creating immunological memory after an initial response to a specific pathogen leading to an enhanced response to subsequent encounters with that pathogen. Increasing evidence has been gathered showing that cells belonging to innate immune system have the ability to regulate adaptive immune response and express features of an immunological memory [1]. NK cells being a part of the innate immune system have been implicated in autoimmune diseases as diabetes, rheumatoid arthritis, and multiple sclerosis [1]. Multiple sclerosis (MS) and its animal model—experimental autoimmune encephalomyelitis (EAE)—have been characterized by inflammation within central nervous system represented by immune cell infiltration, demyelination, and axonal damage, resulting in clinical manifestation of the disease. T lymphocytes are regarded as main immune cells responsible for pathogenic changes in MS [3]

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